Programmed cell death (apoptosis) is an ongoing process in both the developing and the mature nervous system. In the developing nervous system, neurons undergo apoptosis unless they receive an adequate supply of neurotrophic substances from the target (for example, the muscle) that they innervate. In the mature nervous system, apoptosis occurs in the course of neurodegenerative diseases, such as Alzheimer's and Parkinson's Diseases, which progress slowly over long periods of time, and in acute neurological insults, such as a stroke. Understanding how apoptosis is regulated is, therefore, an important step toward developing effective treatments for neurodegenerative diseases and stroke.
Apoptosis can be induced in a number of different cell types by overexpression of a tumor suppressor gene called p53 (reviewed in Elledge et al., Bioessays 17:923-930, 1995; White, Genes Dev. 10:1-15, 1996). Following DNA damage, which may cause the cell to proliferate uncontrollably, p53 is expressed and helps to prevent tumor formation by activating the expression of other genes, such as the cyclin kinase inhibitor p21 (also known as WAF-1), which mediates cell cycle arrest and prevents the propagation of damaged DNA (Harper et al., Cell 75:805-816, 1993; Xiong et al., Nature 366:701-704, 1993). The cellular response to overexpression of p53 may vary however, depending on the cell type; instead of arresting cell growth, p53 overexpression may cause apoptosis (Katayose et al., Int. J. Oncol. 3:781-788, 1995; Picksley et al. Current Opin. Cell Biol. 6:853-858, 1994; White, supra). The precise mechanism by which p53 mediates apoptosis in tumor cells is not well understood, nor is it known whether p53 is directly involved in the apoptosis of postmitotic (i.e., non-proliferating) neurons.
Recently, a number of studies have demonstrated that adenovirus-based vectors can be used to transduce neurons of the CNS that have been placed in culture (Slack et al. Current Opin. Neurobiol., 6:576-583, 1996), but it is not known if these may vectors negatively impact the function of the recipient cell. If adenovirus-derived vectors are to be useful for modulating apoptosis in neurons, their influence on the biochemistry and physiology of the neuron must be understood.